This Funding Opportunity Announcement (FOA) solicits
applications to develop highly innovative computational approaches for
interpreting sequence variants in the non-protein-coding regions of the human
genome. The goal is to develop methods that analyze whole-genome sequence
data by integrating data sets, such as ones on genome function, phenotypes,
patterns of variation, and other features, to identify or substantially narrow
the set of variants that are candidates for affecting organismal function
leading to disease risk or other traits. The accuracy of the computational
approaches developed should be assessed using experimental data.

Key Dates

Posted Date

September 30, 2013

Open Date (Earliest Submission Date)

December 21, 2013

Letter of Intent Due Date(s)

December 21, 2013 and April 21, 2015 per NOT-HG-15-013 (Previously December 21, 2014)

Application Due Date(s)

January 21, 2014 and May 21, 2015 per NOT-HG-15-013 (Previously January 21, 2015), by 5:00 PM local time
of applicant organization.

Applicants are encouraged to apply early to allow adequate
time to make any corrections to errors found in the application during the
submission process by the due date.

AIDS Application Due Date(s)

Not Applicable

Scientific Merit Review

June or July 2014, and October or November 2015 per NOT-HG-15-013 (Previously June or July 2015)

Advisory Council Review

October 2014 and January 2016 per NOT-HG-15-013 (Previously October 2015)

It is critical that applicants follow the instructions in
the SF424
(R&R) Application Guide, except where instructed to do otherwise (in
this FOA or in a Notice from the NIH Guide for Grants and Contracts).
Conformance to all requirements (both in the Application Guide and the FOA)
is required and strictly enforced. Applicants must read and follow all
application instructions in the Application Guide as well as any
program-specific instructions noted in Section
IV. When the program-specific instructions deviate from those in the
Application Guide, follow the program-specific instructions. Applications that
do not comply with these instructions may be delayed or not accepted for review.

This Funding Opportunity Announcement (FOA) solicits
applications to develop highly innovative computational approaches for
interpreting sequence variants in the non-protein-coding regions of the human
genome. The goal is to develop methods that analyze whole-genome sequence data
by integrating data sets, such as ones on genome function, phenotypes, patterns
of variation, and other features, to identify or substantially narrow the set
of variants that are candidates for affecting organismal function leading to
disease risk or other traits. The accuracy of the computational approaches
developed should be assessed using experimental data.

Background

People’s genomes differ at tens of millions of sites, and
interpreting how this variation affects phenotypes and disease risk is extremely
challenging. Although most variants found in genome-wide association studies
(GWAS) to be associated with disease lie outside of protein-coding regions,
most large-scale disease sequencing projects primarily sequence exomes rather
than whole genomes. While the cost difference is one factor, a major reason
for focusing on exomes is the difficulty of interpreting variation in
non-protein-coding regions.

Many researchers are working to predict the organismal
effects of variants in amino-acid sequence. However, this FOA addresses the
even more challenging problem of determining which variants (or substantially
narrowing the set of possible variants) in non-coding regions contribute to
differences in organismal phenotypes and disease risk.

Statistical association of a variant with a disease is a
useful starting point, but it does not prove that the variant contributes to
the pathophysiology of the disease. One challenge is identifying the causal
variants; multiple variants in a region may be statistically associated with
the disease and each other, though only one or a few may contribute to the
disease. Another challenge is predicting functional differences; while some
variants are in putative regulatory elements, we usually do not know how these
variants affect molecular functions, and even if differences in molecular
function are known we do not know how they affect organismal phenotypes.

Integrating genetic variation data with data on genome
function and other data sets can help to narrow the set of candidate variants
that might affect organismal phenotypes. For example, several variants in a
region may have similar associations with a disease, but the set of variants
could be narrowed by including only ones that are conserved among species and that
have histone modifications indicative of regulatory elements. Or variants
associated with a disease might be found near several genes, but the set of
variants affecting organismal function could be narrowed if RNA expression
levels in tissues relevant to that disease differ for only one of these genes.
Thus, analyzing multiple data types should narrow the set of variants
potentially affecting organismal function.

“Proving” the causality of a variant for a difference in
organismal function is extremely challenging. The definitive criteria have not
yet been established. Showing that a molecular phenotype, such as RNA
expression or DNA methylation, differs among individuals differing in genotype
at that variant site is a possible first step, but any effects due to
differences in other variants in linkage disequilibrium would need to be
accounted for, along with various other confounding variables. Even if the
molecular phenotype differs among genotypes, it would need to be shown to cause
the organismal phenotype. This FOA requires that evidence be provided to
assess the accuracy of the computational predictions, but does not require that
the evidence be strong enough to constitute proof of the organismal effect.

Scope of Research

Computational
approaches

This initiative will support the development of
computational methods to interpret whole-genome sequence data by integrating
data sets, such as ones on genome function, phenotypes, patterns of variation,
and other features, to identify, or to substantially narrow, the set of
variants that are candidates for affecting organismal-level traits or
diseases. The methods should be new or substantial improvements, rather than
incremental improvements in existing approaches.

The scale of analysis should be genome-wide interpretation
of the variants that may contribute to the trait or disease being studied,
rather than variants found in a particular gene, gene family, or chromosome
region. The initial approaches should start with the entire genome and narrow
the focus to sets of regions for more analysis, such as by using data from
whole-genome sequencing studies, GWAS studies, or scans for natural selection.
(The focus is on interpreting germline variants; somatic mutations, e.g., in
tumors, raise issues such as heterogeneity that are important but not the focus
of this FOA.)

The focus may be on variants in specific classes of sites,
such as CNVs, transcription-factor binding sites, or CpG islands. The focus of
the proposed methods should be on variants in non-protein-coding regions,
although the genome-wide analysis results may also include variants in coding
regions. (For example, any variants in coding regions should not be studied
for non-synonymous amino acid changes, but may be studied as part of the
general approach or class of sites, such as studying how insertions or
deletions affect chromatin domains rather than their frameshift effects.) The
approaches must be generalizable beyond the specific data sets and traits or
diseases studied.

The data types used could include whole-genome sequence
data, targeted genome sequence data, GWAS genotype and phenotype data,
gene-gene or gene-environment interactions, patterns of variation within and
among populations and species, biochemical pathways, and various functional
data types or molecular phenotypes such as RNA expression, DNA methylation,
transcription-factor binding sites, chromatin structure, and protein
interactions. Other data types may also be proposed. Data from model
organisms may be used for interpreting the human variants. Applicants will
need to explain what data sets they will use and how they will obtain them.
All data sets used should be available to other researchers, at least by the
end of the first year of the award. Relevant data may be obtained from public
resources such as dbGaP, TCGA, 1000 Genomes, GTEx, ENCODE, Roadmap Epigenomics,
LINCS, the Molecular Signatures Database, GEO, brain atlases, and the Human
Connectome.

Applications may identify one or more organismal traits or
diseases to study, such as a human disease, disease resistance, pharmacologic
responses, or physiological traits. Any traits or diseases chosen should be
well-justified, such as by the potential for generalizable results and data
availability. NHGRI solicits applications that investigate any disease or
trait. NCI solicits applications for studies focusing on germline variants related
to cancer susceptibility. NIDA solicits applications for studies related to
drug addiction.

The deliverable should be a generalizable approach to
interpret whole-genome sequence data by integrating various data types to
substantially narrow the set of variants that may contribute to organismal
traits or diseases. Examples of computational approaches that this FOA could
support include those listed below; other approaches are also encouraged.

1. Use GWAS genotype, sequence, and phenotype data to find
genomic regions associated with a disease, and then use several existing –omic
data sets on genome function to narrow the set of variants that potentially
affect organismal function.

2. Use data on chromatin structure to predict where
insertions or deletions affect gene regulation by leading to differences in
open chromosome domains. (This approach is more about molecular than
organismal function; it would need to be combined with other data types to
address organismal function.)

3. Use data on transcription factor binding and RNA
expression to predict how variants in promoters and enhancers affect gene regulation.
(This approach is more about molecular than organismal function; it would need
to be combined with other data types to address organismal function.)

4. Use patterns of variation in populations and species to
find genomic regions that have undergone selection. (This approach will
identify regions containing variants that affect organismal function, but will
not indicate their functions; it could be combined with functional data types.)

5. Use data on epigenomic marks to assess how epigenomic variability
correlates with disease risk.

Experimental
data to assess the computational approaches

Applications should also include production of experimental
data, or use of existing experimental data, to provide evidence about the
sensitivity and specificity of the computational predictions about which
narrower sets of variants contribute to the organismal phenotypes. A variety
of experimental approaches could be used, ranging from methods using less
physiological systems that test many predictions to methods using more
physiological systems to test a few predictions. A mix of approaches may be
used. Such data may also be obtained from patients or from model organisms
such as mouse and zebrafish. The experimental systems need to be
well-justified for the value of the information and the costs.

Some examples of experimental approaches include those
listed below; other approaches are also encouraged. Creativity in
cost-effective tests of the computational predictions is encouraged.

3. Medium-throughput assays in transgenic mice or
zebrafish, testing tens or hundreds of elements, using gene expression or
organismal phenotypes as endpoints.

4. Medium-throughput assays in samples from patients,
testing the consequences of naturally occurring variants on gene expression or
cell function.

5. Low-throughput assays, using mouse DNA deletions or iPS
cells derived from patients, testing a few elements in their natural genomic
settings, which could include gene expression, cell function, or organismal
phenotypes as endpoints.

The experimental data should be used to assess the accuracy
of the computational approaches. The assessment may also provide information
about the conditions that affect the validity of the computational approaches
and other variables that are important (such as that adult zebrafish rather
than juveniles provide more accurate predictions for how variants affect human
phenotypes). The assessment may also suggest additional data types that may be
useful in teasing out causality from statistical associations, or narrowing the
set of variants that may be causal. The experimental data used for assessment are
expected to be released within a year of being produced so that other
researchers can compare methods.

Aside from the experimental work to provide evidence to
assess the predictions, this FOA will not support large-scale data production
or phenotyping, databases, methods to associate variants with disease
independent of functional data, or approaches that simply aggregate information
on variants.

NHGRI will post a list of Frequently Asked Questions (FAQs)
and answers at www.FuncVarRFAHG13-013.nih.gov; this information may be updated
without additional notice.

Section II. Award Information

Funding Instrument

Grant: A support mechanism providing money, property, or
both to an eligible entity to carry out an approved project or activity.

Application Types Allowed

New
Resubmission

The OER
Glossary and the SF424 (R&R) Application Guide provide details on
these application types.

Funds Available and Anticipated Number of Awards

NHGRI, NCI, and NIDA intend to commit $6 million in FY
2015 to fund 7-8 awards, and NHGRI and NIDA intend to commit an additional $5.3
million in FY 2016 to fund 6-7 additional awards.

Award Budget

Applications may request up to $500,000 direct costs per
year.

Award Project Period

Applications may request up to three years of support.

NIH grants policies as
described in the NIH Grants
Policy Statement will apply to the
applications submitted and awards made in response to this FOA.

Section III. Eligibility
Information

1. Eligible Applicants

Eligible Organizations

Higher Education Institutions

Public/State Controlled Institutions of Higher Education

Private Institutions of Higher Education

The following types of Higher Education Institutions
are always encouraged to apply for NIH support as Public or Private
Institutions of Higher Education:

Applicant organizations must complete and maintain the
following registrations as described in the SF 424 (R&R) Application Guide
to be eligible to apply for or receive an award. All registrations must be
completed prior to the application being submitted. Registration can take 6
weeks or more, so applicants should begin the registration process as soon as
possible. The NIH
Policy on Late Submission of Grant Applications states that failure to
complete registrations in advance of a due date is not a valid reason for a
late submission.

Dun and Bradstreet
Universal Numbering System (DUNS) - All registrations require that
applicants be issued a DUNS number. After obtaining a DUNS number, applicants
can begin both SAM and eRA Commons registrations. The same DUNS number must be
used for all registrations, as well as on the grant application.

System for Award Management (SAM) (formerly CCR) – Applicants must complete and maintain an active registration, which requires renewal at least
annually. The renewal process may require as much time as the
initial registration. SAM registration includes the assignment of a Commercial
and Government Entity (CAGE) Code for domestic organizations which have not
already been assigned a CAGE Code.

eRA Commons - Applicants
must have an active DUNS number and SAM registration in order to complete the
eRA Commons registration. Organizations can register with the eRA Commons as
they are working through their SAM or Grants.gov registration. eRA Commons
requires organizations to identify at least one Signing Official (SO) and at
least one Program Director/Principal Investigator (PD/PI) account in order to
submit an application.

Grants.gov – Applicants
must have an active DUNS number and SAM registration in order to complete the Grants.gov
registration.

Program
Directors/Principal Investigators (PD(s)/PI(s))

All PD(s)/PI(s) must have an eRA Commons account and should
work with their organizational officials to either create a new account or to
affiliate an existing account with the applicant organization’s eRA Commons
account. If the PD/PI is also the organizational Signing Official, they must
have two distinct eRA Commons accounts, one for each role. Obtaining an eRA
Commons account can take up to 2 weeks.

Eligible Individuals (Program Director/Principal
Investigator)

Any individual(s) with the skills, knowledge, and resources
necessary to carry out the proposed research as the Program Director(s)/Principal
Investigator(s) (PD(s)/PI(s)) is invited to work with his/her organization to
develop an application for support. Individuals from underrepresented racial
and ethnic groups as well as individuals with disabilities are always
encouraged to apply for NIH support.

Applicant organizations may submit more than one application,
provided that each application is scientifically distinct.

NIH will not accept any application that is essentially the
same as one already reviewed within the past thirty-seven months (as described
in the NIH
Grants Policy Statement), except for submission:

To an RFA of an application that was submitted previously as an
investigator-initiated application but not paid;

Of an investigator-initiated application that was originally
submitted to an RFA but not paid; or

Of an application with a changed grant activity code.

Section IV. Application and Submission Information

1. Requesting an
Application Package

Applicants must download the SF424 (R&R) application
package associated with this funding opportunity using the “Apply for Grant
Electronically” button in this FOA or following the directions provided at Grants.gov.

2. Content and Form of Application Submission

It is critical that applicants follow the instructions in
the SF424
(R&R) Application Guide, except where instructed in this funding
opportunity announcement to do otherwise. Conformance to the requirements in
the Application Guide is required and strictly enforced. Applications that are
out of compliance with these instructions may be delayed or not accepted for
review.

Although a letter of intent is not required, is not binding,
and does not enter into the review of a subsequent application, the information
that it contains allows IC staff to estimate the potential review workload and
plan the review.

By the date listed in Part 1. Overview
Information, prospective applicants are asked to submit a letter of intent
that includes the following information:

All page limitations described in the SF424 Application
Guide and the Table of Page
Limits must be followed.

Required and Optional Components

The forms package associated with this FOA includes all
applicable components, required and optional. Please note that some components
marked optional in the application package are required for submission of
applications for this FOA. Follow all instructions in the SF424 (R&R)
Application Guide to ensure you complete all appropriate “optional” components.

Instructions for Application Submission

The following section supplements the instructions found in
the SF424 (R&R) Application Guide and should be used for preparing an
application to this FOA.

SF424(R&R) Cover

All instructions in the SF424 (R&R) Application Guide
must be followed.

SF424(R&R) Project/Performance Site Locations

All instructions in the SF424 (R&R) Application Guide
must be followed.

SF424(R&R) Other Project Information

All instructions in the SF424 (R&R) Application Guide
must be followed.

SF424(R&R) Senior/Key Person Profile

All instructions in the SF424 (R&R) Application Guide
must be followed.

R&R or Modular Budget

All instructions in the SF424 (R&R) Application Guide
must be followed.

PHS 398 Cover Page Supplement

All instructions in the SF424 (R&R) Application Guide
must be followed.

PHS 398 Research Plan

All instructions in the SF424 (R&R) Application Guide
must be followed, with the following additional instructions:

Research
Strategy: Applicants should describe the timeline for all major
steps in the project.

Applicants should explain what data sets they will use and
how they will obtain them.

Applicants should describe how their methods compare to or
are expected to compare to other methods that address the same question.

Applicants should discuss the scalability of their
computational approaches.

Applicants should explain how the experimental assessments
test the specificity and sensitivity of the computational predictions. They
should justify the assays chosen, based on the trade-offs between throughput
and physiological relevance.

Applicants should justify the allocation
of their budget and resources among development of computational methods,
generation of computational predictions, and experimental assessment.

The proposed research project likely will include the
development of software for the interpretation of non-coding variants.
Software developed by awardees should be modular and robust. To facilitate
broad use, software development should, to the extent possible, use standard
formats for data input and output.

Protection
of Human Subjects: All applicants using human data should
carefully explain how they got the data, whether this is human subjects
research, whether someone in their research group has the individual
identifiers for the data (in which case this is human subjects research), and
whether the data are anonymous or publicly available (in which case this is not
human subjects research). This explanation is required whether or not NIH
rules define the research as involving human subjects.

Resource
Sharing Plan: Individuals are required to comply with the
instructions for the Resource Sharing Plans (Data Sharing Plan, Sharing Model
Organisms, and Genome Wide Association Studies (GWAS)) as provided in the SF424
(R&R) Application Guide, with the following modifications:

All applications, regardless of the amount of direct costs
requested for any one year, should include a Data Sharing Plan, and, if
applicable, a plan for Sharing Model Organisms.

Generally, a GWAS Sharing Plan is expected, but it is not
applicable for this FOA.

NHGRI is committed to the principle of rapid release of data,
experimental protocols, models, and software to the scientific community.
Applicants are expected to provide a plan to release to the research community the
methods, algorithms, software, data, and assessments of the methods in a timely
fashion through an informatics platform.

Applicants who propose to use or develop data sets that are
not publicly shared at the start of the project are expected to describe their
plans for sharing these data sets by the end of the first year of the award.

Plan for Sharing Software: A software dissemination plan,
with appropriate timelines, is expected to be included in the Resource Sharing
Plans to meet the goals of this program. There is no prescribed single license
for software produced in this project; however, reviewers will be asked to
evaluate dissemination plans based on their likely impact. A dissemination
plan guided by the following principles is thought to promote the largest
impact:

1. The software should be freely available to biomedical
researchers and educators in the non-profit sector, such as education
institutions, research institutions, and government laboratories.

2. The terms of software availability should include the
ability of outside researchers to modify the source code and to share
modifications with other colleagues as well as with the investigators. The
terms should also permit the dissemination and commercialization of enhanced or
customized versions of the software, and incorporation of the software or
pieces of it into other software packages.

3. To preserve utility to the community, the software
should be transferable such that another individual or team can continue
development if the original investigators are unwilling or unable to do so.

4. Applicants are expected to propose a plan to manage and
disseminate the improvements or customizations of their tools and resources
that are contributed by others. This proposal may include a plan to incorporate
the enhancements into the “official” core software, may involve the creation of
an infrastructure for plug-ins, or may describe some other solution.

The adequacy of software sharing plans will be considered by
Program staff when making recommendations about funding applications. Program
staff may negotiate modifications of software sharing plans with the Program
Director/Principal Investigator before making recommendations on funding an
application. Any software dissemination plans represent a commitment by the
institution (and its subcontractors as applicable) to support and abide by the
plan. The final versions of any accepted software sharing plans will become a
condition of the award. The effectiveness of software sharing may be evaluated
as part of the administrative review of each Non-Competing Grant Progress
Report (PHS 2590). See Section VI.3., “Reporting”.

Appendix: Do not use the Appendix to circumvent page limits. Follow all
instructions for the Appendix as described in the SF424 (R&R) Application
Guide.

Planned Enrollment Report

When conducting clinical research, follow all instructions
for completing Planned Enrollment Reports as described in the SF424 (R&R)
Application Guide.

PHS 398 Cumulative Inclusion Enrollment Report

When conducting clinical research, follow all instructions
for completing Cumulative Inclusion Enrollment Report
as described in the SF424 (R&R) Application Guide.

Foreign Institutions

Foreign (non-U.S.) institutions must follow policies
described in the NIH Grants
Policy Statement, and procedures for foreign institutions described
throughout the SF424 (R&R) Application Guide.

3. Submission Dates and
Times

Part I. Overview Information contains information about Key Dates. Applicants are encouraged to submit applications
before the due date to ensure they have time to make any application
corrections that might be necessary for successful submission.

Organizations must submit applications to Grants.gov (the online portal to find and apply for grants
across all Federal agencies). Applicants must then complete the submission process by tracking the
status of the application in the eRA Commons, NIH’s electronic system for grants
administration. NIH and Grants.gov systems check the application against many
of the application instructions upon submission. Errors must be corrected and a
changed/corrected application must be submitted to Grants.gov on or before the application
due date. If a Changed/Corrected application is submitted after the deadline,
the application will be considered late.

Applicants
are responsible for viewing their application before the due date in the eRA
Commons to ensure accurate and successful submission.

Information on the submission process and a definition of
on-time submission are provided in the SF424 (R&R) Application Guide.

For assistance with your electronic application or for more information on the electronic submission
process, visit Applying
Electronically.

Important
reminders:All PD(s)/PI(s) must include their eRA Commons ID in the
Credential fieldof the Senior/Key Person Profile Component of the
SF424(R&R) Application Package. Failure to register in the Commons
and to include a valid PD/PI Commons ID in the credential field will prevent
the successful submission of an electronic application to NIH. See Section III of this FOA for information on
registration requirements.

The applicant organization must ensure that the DUNS number it provides on the
application is the same number used in the organization’s profile in the eRA
Commons and for the System for Award Management. Additional information may be
found in the SF424 (R&R) Application Guide.

Upon receipt, applications will be evaluated for
completeness by the Center for Scientific Review and responsiveness by components of participating organizations,
NIH. Applications that are incomplete or nonresponsive will not be reviewed.

Post Submission Materials

Applicants are required to follow the instructions for
post-submission materials, as described in NOT-OD-13-030, with the
following modification:

Applicants may submit late-breaking research findings
(maximum of 2 printed pages) 40 days before the review.

Section V. Application Review Information

1.
Criteria

Only the review criteria described below will be considered
in the review process. As part of the NIH mission,
all applications submitted to the NIH in support of biomedical and behavioral
research are evaluated for scientific and technical merit through the NIH peer
review system.

Overall Impact

Reviewers will provide an overall impact score to reflect
their assessment of the likelihood for the project to exert a sustained,
powerful influence on the research field(s) involved, in consideration of the
following review criteria and additional review criteria (as applicable for the
project proposed).

Scored Review Criteria

Reviewers will consider each of the review criteria below in
the determination of scientific merit, and give a separate score for each. An
application does not need to be strong in all categories to be judged likely to
have major scientific impact. For example, a project that by its nature is not
innovative may be essential to advance a field.

Significance

Does the project address an important problem or a
critical barrier to progress in the field? If the aims of the project are
achieved, how will scientific knowledge, technical capability, and/or clinical practice
be improved? How will successful completion of the aims change the concepts,
methods, technologies, treatments, services, or preventative interventions that
drive this field? Will the computational approaches substantially improve the
ability to characterize the organismal effects of non-coding variants or narrow
the set for further study? Will the experimental data provide useful
information for assessing the experimental approaches?

Investigator(s)

Are the PD(s)/PI(s), collaborators, and other
researchers well suited to the project? If Early Stage Investigators or New
Investigators, or in the early stages of independent careers, do they have
appropriate experience and training? If established, have they demonstrated an
ongoing record of accomplishments that have advanced their field(s)? If the
project is collaborative or multi-PD/PI, do the investigators have
complementary and integrated expertise; are their leadership approach,
governance and organizational structure appropriate for the project? Does the
research team have the computational and experimental expertise needed for the
methods development, data production (or use), and assessment of the
computational methods?

Innovation

Does the application challenge and seek to shift
current research or clinical practice paradigms by utilizing novel theoretical
concepts, approaches or methodologies, instrumentation, or interventions? Are
the concepts, approaches or methodologies, instrumentation, or interventions
novel to one field of research or novel in a broad sense? Is a refinement,
improvement, or new application of theoretical concepts, approaches or
methodologies, instrumentation, or interventions proposed? Will the
computational approaches result in substantial improvements in interpreting
non-coding variants and narrowing the set of variants for further study? Do
the experimental approaches have the level of innovation needed to assess the
computational approaches?

Approach

Are the overall strategy, methodology, and analyses
well-reasoned and appropriate to accomplish the specific aims of the project?
Are potential problems, alternative strategies, and benchmarks for success
presented? If the project is in the early stages of development, will the
strategy establish feasibility and will particularly risky aspects be managed?
Are the components integrated appropriately? How well do the experimental
studies assess the specificity and sensitivity of the computational
predictions? How reasonable are the assays chosen, based on the trade-offs
between throughput and physiological relevance? Will the approaches be useful
beyond the datasets and diseases or traits studied in this application?

If the project involves clinical research, are the plans for 1) protection of
human subjects from research risks, and 2) inclusion of minorities and members
of both sexes/genders, as well as the inclusion of children, justified in terms
of the scientific goals and research strategy proposed?

Environment

Will the scientific environment in which the work
will be done contribute to the probability of success? Are the institutional
support, equipment and other physical resources available to the investigators
adequate for the project proposed? Will the project benefit from unique
features of the scientific environment, subject populations, or collaborative
arrangements?

Additional Review Criteria

As applicable for the project proposed, reviewers will
evaluate the following additional items while determining scientific and
technical merit, and in providing an overall impact score, but will not give
separate scores for these items.

Protections for Human Subjects

For research that involves human subjects but does
not involve one of the six categories of research that are exempt under 45 CFR
Part 46, the committee will evaluate the justification for involvement of human
subjects and the proposed protections from research risk relating to their
participation according to the following five review criteria: 1) risk to
subjects, 2) adequacy of protection against risks, 3) potential benefits to the
subjects and others, 4) importance of the knowledge to be gained, and 5) data
and safety monitoring for clinical trials.

For research that involves human subjects and meets the criteria for one or
more of the six categories of research that are exempt under 45 CFR Part 46,
the committee will evaluate: 1) the justification for the exemption, 2) human
subjects involvement and characteristics, and 3) sources of materials. For
additional information on review of the Human Subjects section, please refer to
the Guidelines
for the Review of Human Subjects.

Inclusion of Women, Minorities, and
Children

When the proposed project involves clinical research,
the committee will evaluate the proposed plans for inclusion of minorities and
members of both genders, as well as the inclusion of children. For additional
information on review of the Inclusion section, please refer to the Guidelines
for the Review of Inclusion in Clinical Research.

Vertebrate Animals

The committee will evaluate the involvement of live
vertebrate animals as part of the scientific assessment according to the
following five points: 1) proposed use of the animals, and species, strains,
ages, sex, and numbers to be used; 2) justifications for the use of animals and
for the appropriateness of the species and numbers proposed; 3) adequacy of
veterinary care; 4) procedures for limiting discomfort, distress, pain and
injury to that which is unavoidable in the conduct of scientifically sound
research including the use of analgesic, anesthetic, and tranquilizing drugs
and/or comfortable restraining devices; and 5) methods of euthanasia and reason
for selection if not consistent with the AVMA Guidelines on Euthanasia. For
additional information on review of the Vertebrate Animals section, please
refer to the Worksheet
for Review of the Vertebrate Animal Section.

Biohazards

Reviewers will assess whether materials or procedures
proposed are potentially hazardous to research personnel and/or the
environment, and if needed, determine whether adequate protection is proposed.

Resubmissions

For Resubmissions, the committee will evaluate the
application as now presented, taking into consideration the responses to
comments from the previous scientific review group and changes made to the project.

Renewals

Not Applicable

Revisions

Not Applicable

Additional Review Considerations

As applicable for the project proposed, reviewers will
consider each of the following items, but will not give scores for these items,
and should not consider them in providing an overall impact score.

Applications from Foreign
Organizations

Reviewers will assess whether the project presents
special opportunities for furthering research programs through the use of
unusual talent, resources, populations, or environmental conditions that exist
in other countries and either are not readily available in the United States or
augment existing U.S. resources.

Select Agent Research

Reviewers will assess the information provided in
this section of the application, including 1) the Select Agent(s) to be used in
the proposed research, 2) the registration status of all entities where Select
Agent(s) will be used, 3) the procedures that will be used to monitor
possession use and transfer of Select Agent(s), and 4) plans for appropriate
biosafety, biocontainment, and security of the Select Agent(s).

Reviewers will consider whether the budget and the
requested period of support are fully justified and reasonable in relation to
the proposed research.

2. Review and Selection
Process

Applications will be evaluated for scientific and technical
merit by (an) appropriate Scientific Review Group(s) convened by NHGRI, in
accordance with NIH peer
review policy and procedures, using the stated review
criteria. Assignment to a Scientific Review Group will be shown in the eRA
Commons.

As part of the scientific peer review, all applications:

May undergo a selection process in which only those applications
deemed to have the highest scientific and technical merit (generally the top
half of applications under review) will be discussed and assigned an overall impact
score.

Will receive a written critique.

Appeals of initial peer review will not be accepted for applications submitted in
response to this FOA.

Applications will be assigned to the appropriate NIH
Institute or Center. Applications will compete for available funds with all
other recommended applications submitted in response to this FOA. Following
initial peer review, recommended applications will receive a second level of
review by the National Advisory Council for Human Genome Research. The
following will be considered in making funding decisions:

Scientific and technical merit of the proposed project as
determined by scientific peer review.

Availability of funds.

Relevance of the proposed project to program priorities.

Programmatic balance.

Adequacy of the proposed software and resource sharing plans.

Synergy with other funded projects.

Responsiveness to the FOA.

3. Anticipated Announcement
and Award Dates

After the peer review of the application is completed, the
PD/PI will be able to access his or her Summary Statement (written critique)
via the eRA
Commons.

If the application is under consideration for funding, NIH
will request "just-in-time" information from the applicant as
described in the NIH Grants
Policy Statement.

A formal notification in the form of a Notice of Award (NoA) will be provided
to the applicant organization for successful applications. The NoA signed by
the grants management officer is the authorizing document and will be sent via
email to the grantee’s business official.

Awardees must comply with any funding restrictions described in Section IV.5. Funding Restrictions. Selection
of an application for award is not an authorization to begin performance. Any
costs incurred before receipt of the NoA are at the recipient's risk. These
costs may be reimbursed only to the extent considered allowable pre-award costs.

When multiple years are involved, awardees will be required
to submit the annual Non-Competing Progress Report (PHS 2590 or RPPR)
and financial statements as required in the NIH Grants
Policy Statement.

A final progress report, invention
statement, and the expenditure data portion of the Federal Financial Report are
required for closeout of an award, as described in the NIH Grants
Policy Statement.

The Federal Funding Accountability and Transparency Act of
2006 (Transparency Act), includes a requirement for awardees of Federal grants
to report information about first-tier subawards and executive compensation
under Federal assistance awards issued in FY2011 or later. All awardees of
applicable NIH grants and cooperative agreements are required to report to
the Federal Subaward Reporting System (FSRS) available at www.fsrs.gov on all subawards over $25,000. See the NIH Grants
Policy Statement for additional information on this reporting
requirement.

Section VII. Agency Contacts

We encourage inquiries concerning this funding opportunity
and welcome the opportunity to answer questions from potential applicants.

Awards are made under the authorization of Sections 301 and
405 of the Public Health Service Act as amended (42 USC 241 and 284) and under
Federal Regulations 42 CFR Part 52 and 45 CFR Parts 74 and 92.